Cooperation of PD-1 and LAG-3 Contributes to T-Cell Exhaustion in Anaplasma marginale-Infected Cattle
- 1 October 2016
- journal article
- Published by American Society for Microbiology in Infection and Immunity
- Vol. 84 (10), 2779-2790
- https://doi.org/10.1128/iai.00278-16
Abstract
The CD4 + T-cell response is central for the control of Anaplasma marginale infection in cattle. However, the infection induces a functional exhaustion of antigen-specific CD4 + T cells in cattle immunized with A. marginale outer membrane proteins or purified outer membranes (OMs), which presumably facilitates the persistence of this rickettsia. In the present study, we hypothesize that T-cell exhaustion following infection is induced by the upregulation of immunoinhibitory receptors on T cells, such as programmed death 1 (PD-1) and lymphocyte activation gene 3 (LAG-3). OM-specific T-cell responses and the kinetics of PD-1-positive (PD-1 + ) LAG-3 + exhausted T cells were monitored in A. marginale -challenged cattle previously immunized with OMs. Consistent with data from previous studies, OM-specific proliferation of peripheral blood mononuclear cells (PBMCs) and interferon gamma (IFN-γ) production were significantly suppressed in challenged animals by 5 weeks postinfection (wpi). In addition, bacteremia and anemia also peaked in these animals at 5 wpi. Flow cytometric analysis revealed that the percentage of PD-1 + LAG-3 + T cells in the CD4 + , CD8 + , and γδ T-cell populations gradually increased and also peaked at 5 wpi. A large increase in the percentage of LAG-3 + γδ T cells was also observed. Importantly, in vitro , the combined blockade of the PD-1 and LAG-3 pathways partially restored OM-specific PBMC proliferation and IFN-γ production at 5 wpi. Taken together, these results indicate that coexpression of PD-1 and LAG-3 on T cells contributes to the rapid exhaustion of A. marginale -specific T cells following infection and that these immunoinhibitory receptors regulate T-cell responses during bovine anaplasmosis.Keywords
Funding Information
- United States Department of Agriculture-NIFA (2010-65119-20456)
- USDA-ARS CRIS (5348-32000-033-00D)
- USDA-ARS-CRIS (5348-32000-033-00D)
- JSPS KAKENHI (25257415)
- Science and Technology Research Promotion Program for Agriculture, Forestry, Fisheries, and Food Industry, Japan (26058B)
- HHS | National Institutes of Health (AI053692)
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